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Anal Bioanal Chem. 2016 Jul;408(18):4845-56. doi: 10.1007/s00216-016-9599-4. Epub 2016 May 16.

First metabolic profile of PV8, a novel synthetic cathinone, in human hepatocytes and urine by high-resolution mass spectrometry.

Author information

1
Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Blvd. Suite 05A721, Baltimore, MD, 21224, USA.
2
Program in Toxicology, University of Maryland Baltimore, Baltimore, MD, 21201, USA.
3
Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, 58758, Linköping, Sweden.
4
Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, 58185, Linköping, Sweden.
5
Department of Sciences, John Jay College of Criminal Justice, City University of New York, New York, NY, 10019, USA.
6
Chemistry and Drug Metabolism, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Blvd. Suite 05A721, Baltimore, MD, 21224, USA. marilyn.huestis@gmail.com.
7
University of Maryland Baltimore School of Medicine, 683 Shore Road, Severna Park, MD, 21146, USA. marilyn.huestis@gmail.com.

Abstract

Novel psychoactive substances (NPS) are ever changing on the drug market, making it difficult for toxicology laboratory methods to stay current with so many new drugs. Recently, PV8, a synthetic pyrrolidinophenone, was detected in seized products in Japan (2013), The Netherlands (2014), and Germany (2014). There are no controlled PV8 administration studies, and no pharmacodynamic and pharmacokinetic data. The objective was to determine PV8's metabolic stability in human liver microsome (HLM) incubation and its metabolism following human hepatocyte incubation and high-resolution mass spectrometry (HRMS) with a Thermo Scientific Q-Exactive. Data were acquired with a full-scan data-dependent mass spectrometry method. Scans were thoroughly data mined with different data processing algorithms and analyzed in WebMetaBase. PV8 exhibited a relatively short 28.8 min half-life, with an intrinsic 24.2 μL/min/mg microsomal clearance. This compound is predicted to be an intermediate clearance drug with an estimated human 22.7 mL/min/kg hepatic clearance. Metabolic pathways identified in vitro included: hydroxylation, ketone reduction, carboxylation, N-dealkylation, iminium formation, dehydrogenation, N-oxidation, and carbonylation. The top three in vitro metabolic pathways were di-hydroxylation > ketone reduction > γ-lactam formation. Authentic urine specimen analyses revealed the top three metabolic pathways were aliphatic hydroxylation > ketone reduction + aliphatic hydroxylation > aliphatic carboxylation, although the most prominent peak was parent PV8. These data provide useful urinary metabolite targets (aliphatic hydroxylation, aliphatic hydroxylation + ketone reduction, aliphatic carboxylation, and di-hydroxylation) for forensic and clinical testing, and focus reference standard companies' synthetic efforts to provide commercially available standards needed for PV8 biological specimen testing. Graphical Abstract Top four PV8 metabolites identified in vitro. Biotransformations highlighted in blue. Markush structures presented when exact location of biotransformation is unknown.

KEYWORDS:

HRMS; Hepatocytes; Metabolic profiling; Novel psychoactive substances; PV8; Synthetic cathinones

PMID:
27185540
DOI:
10.1007/s00216-016-9599-4
[Indexed for MEDLINE]

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